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Significance

We have discovered a molecule derived from DNA-damage repair that can correct the lack of phosphorylation of mutant huntingtin, the cause of Huntington’s disease (HD). In a mouse model, treatment reverses HD-like disease, and we see the lowering of mutant huntingtin levels to normal. The mechanism of this molecule is that it is processed to make a signal for kinase activity essential for repairing DNA. This mechanism is critical when neurons are stressed and have very low or absent energy levels. We propose that this molecule is a type of signaling from DNA-damage repair that occurs at dangerously low ATP levels.

Abstract

The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

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